Abstract
Ischemic stroke is a leading cause of death and disability worldwide with effective acute thrombolytic treatments. However, brain repair mechanisms related to spontaneous or rehabilitation-induced recovery are still under investigation, and little is known about the molecules involved. The present study examines the potential role of angiogenin (ANG), a known regulator of cell function and metabolism linked to neurological disorders, focusing in the neurogenic subventricular zone (SVZ). Angiogenin expression was examined in the mouse SVZ and in SVZ-derived neural stem cells (NSCs), which were exposed to exogenous ANG treatment during neurosphere formation as well as in other neuron-like cells (SH-SY5Y). Additionally, male C57Bl/6 mice underwent a distal permanent occlusion of the middle cerebral artery to study endogenous and exercise-induced expression of SVZ-ANG and neuroblast migration. Our results show that SVZ areas are rich in ANG, primarily expressed in DCX+ neuroblasts but not in nestin+NSCs. In vitro, treatment with ANG increased the number of SVZ-derived NSCs forming neurospheres but could not modify SH-SY5Y neurite differentiation. Finally, physical exercise rapidly increased the amount of endogenous ANG in the ipsilateral SVZ niche after ischemia, where DCX-migrating cells increased as part of the post-stroke neurogenesis process. Our findings position for the first time ANG in the SVZ during post-stroke recovery, which could be linked to neurogenesis.
Highlights
Stroke affects 15 million people worldwide annually, and it is a leading cause of long-term disability in industrialized countries [1, 2]
We examined for the first time the presence of ANG in this subventricular zone (SVZ) neurogenic site with the hypothesis that angiogenin could be involved in the regulation of neural precursors, which are known to respond to brain injury or physical exercise
We describe that (i) for the first time, angiogenin is expressed in the adult SVZ, (ii) angiogenin increases the neural stem cells (NSCs) yields in SVZ-derived neurosphere cultures, (iii) angiogenin is overexpressed after physical exercise in the SVZ of the ischemic hemisphere during neurogenesis, and (iv) SVZ angiogenin is mainly expressed in DCX+ neuroblasts
Summary
Stroke affects 15 million people worldwide annually, and it is a leading cause of long-term disability in industrialized countries [1, 2]. The narrow time window limits these strategies, and only a small number of patients benefit from them. These vessel-recanalization strategies are effective, a large percentage of stroke survivors still suffer from motor disabilities and neurological deficits. With this scenario, the only proven effective treatment for disabled stroke patients is rehabilitation, which aims to compensate for the affected sensory-motor function and improve life quality and independence for daily activities [6, 7].
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